tbuckley/cabot-search huggingface dataset:
Photopolymerizable Hydrogel for Enhanced Intramyocardial Vascular Progenitor Cell Delivery and Post‐Myocardial Infarction Healing
Authors: Xuechong Hong, Allen Chilun Luo, Ilias Doulamis, Nicholas Oh, Gwang‐Bum Im, Chun‐Yen Lin, Pedro J. del Nido, Ruei‐Zeng Lin, Juan M. Melero‑Martin
Journal: Advanced Healthcare Materials (2023)

Cell transplantation success for myocardial infarction (MI) treatment is often hindered by low engraftment due to washout effects during myocardial contraction. A clinically viable biomaterial that enhances cell retention can optimize intramyocardial cell delivery. In this study, a therapeutic cell delivery method is developed for MI treatment utilizing a photocrosslinkable gelatin methacryloyl (GelMA) hydrogel. Human vascular progenitor cells, capable of forming functional vasculatures upon transplantation, are combined with an in situ photopolymerization approach and injected into the infarcted zones of mouse hearts. This strategy substantially improves acute cell retention and promotes long-term post-MI cardiac healing, including stabilized cardiac functions, preserved viable myocardium, and reduced cardiac fibrosis. Additionally, engrafted vascular cells polarize recruited bone marrow-derived neutrophils toward a non-inflammatory phenotype via transforming growth factor beta (TGFβ) signaling, fostering a pro-regenerative microenvironment. Neutrophil depletion negates the therapeutic benefits generated by cell delivery in ischemic hearts, highlighting the essential role of non-inflammatory, pro-regenerative neutrophils in cardiac remodeling. In conclusion, this GelMA hydrogel-based intramyocardial vascular cell delivery approach holds promise for enhancing the treatment of acute myocardial infarction.
Biomechanics, Energetics, and Structural Basis of Rupture of Fibrin Networks
Authors: Ranjini K. Ramanujam, Farkhad Maksudov, Rustem I. Litvinov, Chandrasekaran Nagaswami, John W. Weisel, Valerie Tutwiler, Valeri Barsegov
Journal: Advanced Healthcare Materials (2023)

Abstract Fibrin provides the main structural integrity and mechanical strength to blood clots. Failure of fibrin clots can result in life‐threating complications, such as stroke or pulmonary embolism. The dependence of rupture resistance of fibrin networks (uncracked and cracked) on fibrin(ogen) concentrations in the (patho)physiological 1–5 g L −1 range is explored by performing the ultrastructural studies and theoretical analysis of the experimental stress–strain profiles available from mechanical tensile loading assays. Fibrin fibers in the uncracked network stretched evenly, whereas, in the cracked network, fibers around the crack tip showed greater deformation. Unlike fibrin fibers in cracked networks formed at the lower 1–2.7 g L −1 fibrinogen concentrations, fibers formed at the higher 2.7–5 g L −1 concentrations align and stretch simultaneously. Cracked fibrin networks formed in higher fibrinogen solutions are tougher yet less extensible. Statistical modeling revealed that the characteristic strain for fiber alignment, crack size, and fracture toughness of fibrin networks control their rupture resistance. The results obtained provide a structural and biomechanical basis to quantitatively understand the material properties of blood plasma clots and to illuminate the mechanisms of their rupture.
PB1833: STREAMLINED WORKFLOW FOR ANALYZING AND REPORTING OPTICAL GENOME MAPPING FOR HEMATOLOGICAL MALIGNANCIES IN BIONANO VIA SOFTWARE
Authors: Alex Hastie, Alicia Bertolotti, Jen Hauenstein, Andy Wing Chun Pang, Niel Miller, Alka Chaubey
Journal: HemaSphere (2023)

Topic: 3. Acute myeloid leukemia - Biology & Translational Research Background: Optical genome mapping (OGM) can detect all classes of SVs at high resolution, which adds significant insight to assessment of hematological malignancies. Although these novel SVs will help better describe genetic contributions to disease, it can take significant time to curate and classify variants with pathogenicity or of uncertain significance. Aims: We have developed a streamlined workflow for use with Bionano VIA™ software for a comprehensive assessment of relevant SVs in a hematological malignancy genome. Methods: First, by employing disease-specific decision trees for variants published in guidelines for those conditions, the software automatically flags Tier 1A variants detected according to ACMG/AMP/CGC criteria. Second, the overall genome complexity is assessed by observing chromosomal abnormalities detected by OGM. Large events (>5Mb) are counted, and complex genomes are assigned if there are more than 3 or 5 events, depending on the cancer type. Third, calls are further refined by filtering on a pan-cancer specific list to capture those variants that are then manually classified as Tier 1B or 2 by the analyst. Results: Bionano VIA software is also able to accommodate multiple platforms simultaneously (e.g. NGS panels) to provide users a truly comprehensive view of genomic aberrations relevant to hematological malignancies. Summary/Conclusion: This workflow is intended to streamline and simplify analysis and automate visualization, analysis, interpretation and reporting of samples, which are often extremely complex and require extensive manual curation. Keywords: Hematological malignancy, Heme
Cardiopulmonary Performance Among Heart Failure Patients Before and After Left Ventricular Assist Device Implantation
Authors: Cole Buchanan, Collen Buchanan, Maeveen Riordan, Jessica Byrd, Margaret Schulte, Wendy M. Kohrt, Amrut V. Ambardekar, Larry A. Allen, Gene Wolfel, Justin Lawley, Benjamin D. Levine, William K. Cornwell
Journal: JACC Heart Failure (2023)
A complement atlas identifies interleukin-6–dependent alternative pathway dysregulation as a key druggable feature of COVID-19
Authors: Karel F. A. Van Damme, Levi Hoste, Jozefien Declercq, Elisabeth De Leeuw, Bastiaan Maes, Liesbet Martens, Roos Colman, Robin Browaeys, Cédric Bosteels, Stijn Verwaerde, Nicky Vermeulen, Sahine Lameire, Nincy Debeuf, Julie Deckers, Patrick Stordeur, Pieter Depuydt, Eva Van Braeckel, Linos Vandekerckhove, Martin Guilliams, Sjoerd T. T. Schetters, Filomeen Haerynck, Simon J. Tavernier, Bart N. Lambrecht
Journal: Science Translational Medicine (2023)

Improvements in COVID-19 treatments, especially for the critically ill, require deeper understanding of the mechanisms driving disease pathology. The complement system is not only a crucial component of innate host defense but can also contribute to tissue injury. Although all complement pathways have been implicated in COVID-19 pathogenesis, the upstream drivers and downstream effects on tissue injury remain poorly defined. We demonstrate that complement activation is primarily mediated by the alternative pathway, and we provide a comprehensive atlas of the complement alterations around the time of respiratory deterioration. Proteomic and single-cell sequencing mapping across cell types and tissues reveals a division of labor between lung epithelial, stromal, and myeloid cells in complement production, in addition to liver-derived factors. We identify IL-6 and STAT1/3 signaling as an upstream driver of complement responses, linking complement dysregulation to approved COVID-19 therapies. Furthermore, an exploratory proteomic study indicates that inhibition of complement C5 decreases epithelial damage and markers of disease severity. Collectively, these results support complement dysregulation as a key druggable feature of COVID-19.
Targeting sulfation-dependent mechanoreciprocity between matrix and osteoblasts to mitigate bone loss
Authors: Chao Zheng, He Liu, Pianpian Zhao, Weiguang Lu, Shiju Song, Ting He, Jing Fan, Di Wang, Pengfei Yang, Qiang Jie, Hou-Feng Zheng, Zhuojing Luo, Liu Yang
Journal: Science Translational Medicine (2023)

Sulfation is a widespread modification of biomolecules that has been incompletely explored to date. Through cross-phenotype meta-analysis of bone mineral density in up to 426,824 genotyped human participants along with phenotypic characterization of multiple mutant mouse lines, we identified a causative role for sulfate transporter solute carrier family 26 member A2 ( SLC26A2 ) deficiency in osteoporosis. Ablation of SLC26A2 in osteoblasts caused severe bone loss and accumulation of immature bone cells and elicited peculiar pericellular matrix (PCM) production characterized by undersulfation coupled with decreased stiffness. These altered chemophysical properties of the PCM disrupted the formation of focal adhesions in osteoblasts. Bulk RNA sequencing and functional assays revealed that the mechanoreciprocal inhibition of focal adhesion kinase (FAK) and Yes1-associated transcriptional regulator (YAP)/WW domain containing transcription regulator 1 (TAZ) signaling impinged osteoblast maturation upon SLC26A2 deficiency. Moreover, pharmacological abrogation of the Hippo kinases and forced wheel-running ameliorated SLC26A2 -deficient osteoporosis by promoting YAP/TAZ activity. Analysis of mouse single-cell RNA sequencing data suggested coordination among sulfate metabolism, focal adhesion, and YAP/TAZ activity during osteoblast-to-osteocyte transition. In addition to the SLC26A2 -deficient setting, altered FAK and YAP/TAZ signaling was also observed in bone cells of ovariectomized mice and patients with osteoporosis, and pharmacological enforcing of YAP/TAZ activity ameliorated bone loss in ovariectomized mice. Collectively, these data unveil a role for sulfation in the developmental mechanoreciprocity between matrix and osteoblasts, which could be leveraged to prevent bone loss.
The RSVPreF3-AS01 vaccine elicits broad neutralization of contemporary and antigenically distant respiratory syncytial virus strains
Authors: Lionel Sacconnay, Jonathan De Smedt, Vera Rocha-Perugini, Edison Ong, Romuald Mascolo, Anne Atas, Carline Vanden Abeele, Magali de Heusch, Nathalie De Schrevel, Marie-Pierre David, Badiaa Bouzya, Kim Stobbelaar, Yannick Vanloubbeeck, Peter L. Delputte, Corey P. Mallett, Nancy Dezutter, Lucile Warter
Journal: Science Translational Medicine (2023)

The RSVPreF3-AS01 vaccine, containing the respiratory syncytial virus (RSV) prefusion F protein and the AS01 adjuvant, was previously shown to boost neutralization responses against historical RSV strains and to be efficacious in preventing RSV-associated lower respiratory tract diseases in older adults. Although RSV F is highly conserved, variation does exist between strains. Here, we characterized variations in the major viral antigenic sites among contemporary RSV sequences when compared with RSVPreF3 and showed that, in older adults, RSVPreF3-AS01 broadly boosts neutralization responses against currently dominant and antigenically distant RSV strains. RSV-neutralizing responses are thought to play a central role in preventing RSV infection. Therefore, the breadth of RSVPreF3-AS01–elicited neutralization responses may contribute to vaccine efficacy against contemporary RSV strains and those that may emerge in the future.
Diagnosis of cardiovascular disease in patients with chronic kidney disease
Authors: Carmine Zoccali, Patrick B. Mark, Pantelis Sarafidis, Rajiv Agarwal, Marcin Adamczak, Rodrigo Bueno de Oliveira, Ziad A. Massy, Peter Kotanko, Charles J. Ferro, Christoph Wanner, Michel Burnier, Raymond Vanholder, Francesca Mallamaci, Andrzej Wiecek
Journal: Nature Reviews Nephrology (2023)
Reply to F. Poizeau et al
Authors: Lawson Eng, Rinku Sutradhar, Monika K. Krzyzanowska
Journal: Journal of Clinical Oncology (2023)

We thank the readers for their constructive feedback regarding our recent analysis evaluating the impact of antibiotic exposure before immune checkpoint inhibitor (ICI) exposure on overall survival using population-level administrative data from Ontario. 1 This is an area of increasing importance, given the rise of ICI use in cancer care and recognition of the potential role of the gut microbiome.We recognize that there are limitations to using and interpreting population-level observational studies including confounding bias.One major confounding factor is poor general condition or overall health status as these patients are more likely to receive both antibiotics, and this is also associated with reduced survival.The letter by Poizeau et al, 2 references their previous study performing a similar analysis in patients with melanoma with the French National Health Insurance Database; using an overlap weighting propensity score analysis for patients to control for confounding by indication, they demonstrated that prior antibiotic exposure did not influence ICI outcomes. 3Although this is one approach toward controlling for health status, we have attempted to account for it in our multivariable regression analyses by adjusting for covariates related to health status available in our population-level administrative databases selected using both backward selection and clinical judgment.These variables included age, body mass index, the John Hopkin's Aggregate Diagnosis Group score (which is a previously validated comorbidity score for administrative data and uses a similar approach to Poizeau et al 2 to identify comorbidities 3,4 ), and hospitalization within the year before starting ICI.We recognize that sites of metastatic disease and disease burden are prognostic and associated with health status, but these data are not available through our administrative data holdings.There are different tradeoffs to either using propensity score analysis versus regression modeling to adjust for confounders, 5,6 but one of the main limitations of both approaches are unmeasured confounders, which can be difficult to assess using available administrative data.
Saponin-based adjuvants enhance antigen cross-presentation in human CD11c<sup>+</sup>CD1c<sup>+</sup>CD5<sup>−</sup>CD163<sup>+</sup>conventional type 2 dendritic cells
Authors: Nataschja I Ho, Lisa G M Huis in 't Veld, Jesper van Eck van der Sluijs, Branco M H Heuts, Maaike W G Looman, Esther D Kers-Rebel, Koen van den Dries, Harry Dolstra, Joost H A Martens, Willemijn Hobo, Gosse J Adema
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Adjuvants are key for effective vaccination against cancer and chronic infectious diseases. Saponin-based adjuvants (SBAs) are unique among adjuvants in their ability to induce robust cell-mediated immune responses in addition to antibody responses. Recent preclinical studies revealed that SBAs induced cross-presentation and lipid bodies in otherwise poorly cross-presenting CD11b + murine dendritic cells (DCs). Method Here, we investigated the response of human DC subsets to SBAs with RNA sequencing and pathway analyses, lipid body induction visualized by laser scanning microscopy, antigen translocation to the cytosol, and antigen cross-presentation to CD8 + T cells. Results RNA sequencing of SBA-treated conventional type 1 DC (cDC1) and type 2 DC (cDC2) subsets uncovered that SBAs upregulated lipid-related pathways in CD11c + CD1c + cDC2s, especially in the CD5 − CD163 + CD14 + cDC2 subset. Moreover, SBAs induced lipid bodies and enhanced endosomal antigen translocation into the cytosol in this particular cDC2 subset. Finally, SBAs enhanced cross-presentation only in cDC2s, which requires the CD163 + CD14 + cDC2 subset. Conclusions These data thus identify the CD163 + CD14 + cDC2 subset as the main SBA-responsive DC subset in humans and imply new strategies to optimize the application of saponin-based adjuvants in a potent cancer vaccine.
hMENA isoforms regulate cancer intrinsic type I IFN signaling and extrinsic mechanisms of resistance to immune checkpoint blockade in NSCLC
Authors: Paola Trono, Annalisa Tocci, Belinda Palermo, Anna Di Carlo, Lorenzo D'Ambrosio, Daniel D'Andrea, Francesca Di Modugno, Francesca De Nicola, Frauke Goeman, Giacomo Corleone, Sarah Warren, Francesca Paolini, Mariangela Panetta, Isabella Sperduti, Silvia Baldari, Paolo Visca, Silvia Carpano, Federico Cappuzzo, Vincenzo Russo, Claudio Tripodo, Paolo Zucali, Vanesa Gregorc, Federica Marchesi, Paola Nistico
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Understanding how cancer signaling pathways promote an immunosuppressive program which sustains acquired or primary resistance to immune checkpoint blockade (ICB) is a crucial step in improving immunotherapy efficacy. Among the pathways that can affect ICB response is the interferon (IFN) pathway that may be both detrimental and beneficial. The immune sensor retinoic acid-inducible gene I (RIG-I) induces IFN activation and secretion and is activated by actin cytoskeleton disturbance. The actin cytoskeleton regulatory protein hMENA, along with its isoforms, is a key signaling hub in different solid tumors, and recently its role as a regulator of transcription of genes encoding immunomodulatory secretory proteins has been proposed. When hMENA is expressed in tumor cells with low levels of the epithelial specific hMENA 11a isoform, identifies non-small cell lung cancer (NSCLC) patients with poor prognosis. Aim was to identify cancer intrinsic and extrinsic pathways regulated by hMENA 11a downregulation as determinants of ICB response in NSCLC. Here, we present a potential novel mechanism of ICB resistance driven by hMENA 11a downregulation. Methods Effects of hMENA 11a downregulation were tested by RNA-Seq, ATAC-Seq, flow cytometry and biochemical assays. ICB-treated patient tumor tissues were profiled by Nanostring IO 360 Panel enriched with hMENA custom probes. OAK and POPLAR datasets were used to validate our discovery cohort. Results Transcriptomic and biochemical analyses demonstrated that the depletion of hMENA 11a induces IFN pathway activation, the production of different inflammatory mediators including IFNβ via RIG-I, sustains the increase of tumor PD-L1 levels and activates a paracrine loop between tumor cells and a unique macrophage subset favoring an epithelial-mesenchymal transition (EMT). Notably, when we translated our results in a clinical setting of NSCLC ICB-treated patients, transcriptomic analysis revealed that low expression of hMENA 11a , high expression of IFN target genes and high macrophage score identify patients resistant to ICB therapy. Conclusions Collectively, these data establish a new function for the actin cytoskeleton regulator hMENA 11a in modulating cancer cell intrinsic type I IFN signaling and extrinsic mechanisms that promote protumoral macrophages and favor EMT. These data highlight the role of actin cytoskeleton disturbance in activating immune suppressive pathways that may be involved in resistance to ICB in NSCLC.
Hepatorenal Syndrome–Acute Kidney Injury in Liver Transplantation
Authors: Blanca Lizaola-Mayo, Hugo E. Vargas
Journal: Clinical Gastroenterology and Hepatology (2023)

Hepatorenal syndrome (HRS) is a serious complication of cirrhosis. HRS nomenclature has recently changed to HRS-AKI (acute kidney injury). HRS is a complex response to chronic vasodilatory changes brought about by portal hypertension and exacerbated by inflammatory responses that portends poor prognosis to patients with cirrhosis. This syndrome is commonly seen in the setting of infections, particularly spontaneous bacterial peritonitis. Because of the frequency of renal injury in the patient with cirrhosis, HRS-AKI has to be considered high in the differential diagnosis of AKI. Discontinuation of potential triggering agents and elimination of pre-renal AKI, intrinsic renal disease, and structural uropathy as causes of injury are imperative on presentation. Volume expansion with albumin and vasoconstrictive drugs to counteract the underlying splanchnic vasodilation constitutes the most effective medical modality to manage this process. Although the most effective therapy is generally considered to be liver transplantation (LT), the logistic barriers of offering this life-saving therapy on time to all needing it is a major limitation. Terlipressin has been shown to reverse HRS-AKI in a significant proportion of those treated and consequently can lead to increased LT patient survival and freedom from renal replacement therapy. We will review the impact of HRS on the management of patients awaiting LT, present strategies to prevent this significant complication, and discuss major implications of recent therapeutic advances in the setting of LT.
Current Pharmacologic Therapies for Hepatorenal Syndrome-Acute Kidney Injury
Authors: Nikki Duong, Payal Kakadiya, Jasmohan S. Bajaj
Journal: Clinical Gastroenterology and Hepatology (2023)

Hepatorenal syndrome (HRS) can occur in patients with cirrhosis and ascites due to splanchnic vasodilation, renal hypoperfusion, and vasoconstriction. HRS is a diagnosis of exclusion and portends a poor prognosis, with upward of 80% mortality at 2 weeks without treatment. This review will highlight randomized controlled trials for HRS pharmacotherapy.A PubMed review of randomized controlled trials conducted over the past 25 years was undertaken; 18 studies were included.Initial studies showed that norepinephrine is as effective as terlipressin for HRS reversal. Midodrine with octreotide and albumin is less effective than terlipressin but better than albumin alone at improving 30-day mortality. Recently, terlipressin with albumin led to significantly higher rates of HRS reversal compared to albumin alone. Non-response to terlipressin can predict 90-day mortality in acute-on-chronic-liver failure.Our current understanding of HRS treatment is improved by recent randomized clinical trials. Previous studies using varying medication doses along with the "old" definition of hepatorenal syndrome (HRS type 1) rather than HRS-AKI means that there is still a need for future multicenter prospective studies further refining the risk-benefit ratio of vasoconstrictors for HRS-AKI patients. The Food and Drug Administration has approved terlipressin for use in September 2022. Because it will take time to adapt into clinical practice, less cost-prohibitive vasoconstrictors should still be considered. Opportunities also exist to clarify the safety, timing of initiation, as well as possible discontinuation of terlipressin.
Partial gene suppression improves identification of cancer vulnerabilities when CRISPR-Cas9 knockout is pan-lethal
Authors: J. Michael Krill-Burger, Joshua M. Dempster, Ashir A. Borah, Brenton R. Paolella, David E. Root, Todd R. Golub, Jesse S. Boehm, William C. Hahn, James M. McFarland, Francisca Vazquez, Aviad Tsherniak
Journal: Genome biology (2023)

Hundreds of functional genomic screens have been performed across a diverse set of cancer contexts, as part of efforts such as the Cancer Dependency Map, to identify gene dependencies-genes whose loss of function reduces cell viability or fitness. Recently, large-scale screening efforts have shifted from RNAi to CRISPR-Cas9, due to superior efficacy and specificity. However, many effective oncology drugs only partially inhibit their protein targets, leading us to question whether partial suppression of genes using RNAi could reveal cancer vulnerabilities that are missed by complete knockout using CRISPR-Cas9. Here, we compare CRISPR-Cas9 and RNAi dependency profiles of genes across approximately 400 matched cancer cell lines.We find that CRISPR screens accurately identify more gene dependencies per cell line, but the majority of each cell line's dependencies are part of a set of 1867 genes that are shared dependencies across the entire collection (pan-lethals). While RNAi knockdown of about 30% of these genes is also pan-lethal, approximately 50% have selective dependency patterns across cell lines, suggesting they could still be cancer vulnerabilities. The accuracy of the unique RNAi selectivity is supported by associations to multi-omics profiles, drug sensitivity, and other expected co-dependencies.Incorporating RNAi data for genes that are pan-lethal knockouts facilitates the discovery of a wider range of gene targets than could be detected using the CRISPR dataset alone. This can aid in the interpretation of contrasting results obtained from CRISPR and RNAi screens and reinforce the importance of partial gene suppression methods in building a cancer dependency map.